U.S. patent number 7,223,753 [Application Number 10/703,556] was granted by the patent office on 2007-05-29 for diazabicyclic biaryl derivatives.
This patent grant is currently assigned to Neurosearch A/S. Invention is credited to Philip K. Ahring, Tino Dyhring Joergensen, Elsebet Oestergaard Nielsen, Gunnar M. Olsen, Dan Peters.
United States Patent |
7,223,753 |
Peters , et al. |
May 29, 2007 |
Diazabicyclic biaryl derivatives
Abstract
This invention relates to novel diazabicyclic biaryl
derivatives, which are found to be cholinergic ligands at the
nicotinic acetylcholine receptors and modulators of the monoamine
receptors and transporters. Due to their pharmacological profile
the compounds of the invention may be useful for the treatment of
diseases or disorders as diverse as those related to the
cholinergic system of the central nervous system (CNS), the
peripheral nervous system (PNS), diseases or disorders related to
smooth muscle contraction, endocrine diseases or disorders,
diseases or disorders related to neuro-degeneration, diseases or
disorders related to inflammation, pain, and withdrawal symptoms
caused by the termination of abuse of chemical substances.
Inventors: |
Peters; Dan (Malmoe,
SE), Olsen; Gunnar M. (Smoerum, DK),
Nielsen; Elsebet Oestergaard (Koebenhavn K, DK),
Joergensen; Tino Dyhring (Solroed Strand, DK),
Ahring; Philip K. (Bagsvaerd, DK) |
Assignee: |
Neurosearch A/S (Ballerup,
DK)
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Family
ID: |
32659649 |
Appl.
No.: |
10/703,556 |
Filed: |
November 10, 2003 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20040127491 A1 |
Jul 1, 2004 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60426387 |
Nov 15, 2002 |
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Foreign Application Priority Data
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Nov 11, 2002 [DK] |
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PA 2002 01737 |
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Current U.S.
Class: |
514/221; 540/472;
544/349; 540/556; 514/249 |
Current CPC
Class: |
A61K
31/551 (20130101); A61P 25/00 (20180101); C07D
471/08 (20130101); C07D 487/08 (20130101) |
Current International
Class: |
A61P
25/00 (20060101); A61K 31/495 (20060101); A61K
31/551 (20060101); C07D 243/00 (20060101); C07D
471/00 (20060101) |
Field of
Search: |
;514/221,249
;540/472,556 ;544/349 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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101 62 442 |
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Jul 2003 |
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DE |
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1 219 622 |
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Jul 2002 |
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EP |
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WO 00/34279 |
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Jun 2000 |
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WO |
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WO 01/92259 |
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Dec 2001 |
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WO |
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WO 01/92260 |
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Dec 2001 |
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WO |
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WO 01/92261 |
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Dec 2001 |
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WO |
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WO 03/044019 |
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May 2003 |
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WO |
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WO 03/044020 |
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May 2003 |
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WO |
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WO 03/044024 |
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May 2003 |
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WO |
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WO 2004/029053 |
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Apr 2004 |
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WO |
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Primary Examiner: Coleman; Brenda
Attorney, Agent or Firm: Birch, Stewart, Kolasch &
Birch, LLP
Parent Case Text
This Nonprovisional application claims priority under 35 U.S.C.
.sctn. 119(e) to U.S. Provisional Application Ser. No. 60/426,387
filed on Nov. 15, 2002, the entire contents of which are hereby
incorporated by reference.
Claims
The invention claimed is:
1. A diazabicyclic biaryl compound represented by Formula I
##STR00041## any of its enantiomers or any mixture of its
enantiomers, or a pharmaceutically acceptable salt thereof, wherein
n is 1, 2 or 3; and 'A'' represents a bivalent phenyl group of the
formula ##STR00042## 'A'' represents a bivalent 6-membered aromatic
monocyclic carbocyclic or heterocyclic group selected from
##STR00043## (read in the direction represented by ' and ''); and B
represents a phenyl group; or B represents a 5-membered aromatic
monocyclic heterocyclic group selected from ##STR00044## B
represents a 6-membered aromatic monocyclic heterocyclic group
selected from ##STR00045## B represents an indol-2-yl, an
indol-3-yl, and indol-5-yl, or an indol-6-yl group.
2. The diazabicyclic biaryl compound of claim 1, which is
4-(6-Thien-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Pyridin-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Selenophen-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6Furan-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Thien-2-yl-pyridazin-3-yl)-1,4-diazabicyelo[3.2.2]nonane;
4-(6-Furan-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6Thiazol-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Selenophen-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Indol-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Indol-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Indol-5-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Indol-6-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-oxazol-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-oxazol-5-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6thiazol-5-yl-pyridazin-3-yl)-1,4-diazabicycio[3.2.2]nonane;
4-[(6-(1,3,4)-thiadiazol-2-yl]-pyridazin-3-yl-1,4-diazabicyclo[3.2.2]nona-
ne; or
4-[6-(1,3,4)-oxadiazol-2-yl]-pyridazin-3-yl-1,4-diazabieyelo[3.2.2]-
nonane; or an enantiomer or a mixture of its enantiomers, or a
pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition comprising a therapeutically
effective amount of a diazabicyclic biaryl compound of claim 1, or
a pharmaceutically-acceptable addition salt thereof, together with
at least one pharmaceutically-acceptable carrier or diluent.
4. A method of treatment of a disease or a disorder or a condition
of a living animal body, including a human, wherein the disease,
disorder or condition is responsive to modulation of cholinergic
receptors and/or monoamine receptors and wherein the disease,
disorder, or condition is selected from the group consisting of
Alzheimer's disease and Parkinson's disease, which method comprises
the step of administering to a living animal body in need thereof a
therapeutically effective amount of a diazabicyclic biaryl compound
of claim 1.
Description
TECHNICAL FIELD
This invention relates to novel diazabicyclic biaryl derivatives,
which are found to be cholinergic ligands at the nicotinic
acetylcholine receptors and modulators of the monoamine receptors
and transporters. Due to their pharmacological profile the
compounds of the invention may be useful for the treatment of
diseases or disorders as diverse as those related to the
cholinergic system of the central nervous system (CNS), the
peripheral nervous system (PNS), diseases or disorders related to
smooth muscle contraction, endocrine diseases or disorders,
diseases or disorders related to neuro-degeneration, diseases or
disorders related to inflammation, pain, and withdrawal symptoms
caused by the termination of abuse of chemical substances.
BACKGROUND ART
The endogenous cholinergic neurotransmitter, acetylcholine, exert
its biological effect via two types of cholinergic receptors, the
muscarinic Acetyl Choline Receptors (mAChR) and the nicotinic
Acetyl Choline Receptors (nAChR).
As it is well established that muscarinic acetylcholine receptors
dominate quantitatively over nicotinic acetylcholine receptors in
the brain area important to memory and cognition, and much research
aimed at the development of agents for the treatment of memory
related disorders have focused on the synthesis of muscarinic
acetylcholine receptor modulators.
Recently, however, an interest in the development of nAChR
modulators has emerged. Several diseases are associated with
degeneration of the cholinergic system i.e. senile dementia of the
Alzheimer type, vascular dementia and cognitive impairment due to
the organic brain damage disease related directly to alcoholism.
Indeed several CNS disorders can be attributed to a cholinergic
deficiency, a dopaminergic deficiency, an adrenergic deficiency or
a serotonergic deficiency.
WO 00/34279, WO 01/92259, WO 01/92260, WO 01/92261, WO 03/044019,
WO 03/044020, WO 03/044024 (Sanofi-Synthelabo), and DE 10162442
(Bayer AG) describe 1,4-diazabicyclo[3.3.2]nonane derivatives
having affinity for nicotinic receptors.
SUMMARY OF THE INVENTION
The present invention is devoted to the provision novel modulators
of the nicotinic and/or of the monoamine receptors, which
modulators are useful for the treatment of diseases or disorders
related to the cholinergic receptors, and in particular the
nicotinic acetylcholine receptor (nAChR), the serotonin receptor
(5-HTR), the dopamine receptor (DAR) and the norepinephrine
receptor (NER), and of the biogenic amine transporters for
serotonin (5-HT), dopamine (DA) and norepinephrine (NE).
Due to their pharmacological profile the compounds of the invention
may be useful for the treatment of diseases or disorders as diverse
as those related to the cholinergic system of the central nervous
system (CNS), the peripheral nervous system (PNS), diseases or
disorders related to smooth muscle contraction, endocrine diseases
or disorders, diseases or disorders related to neuro-degeneration,
diseases or disorders related to inflammation, pain, and withdrawal
symptoms caused by the termination of abuse of chemical
substances.
The compounds of the invention may also be useful as diagnostic
tools or monitoring agents in various diagnostic methods, and in
particular for in vivo receptor imaging (neuroimaging), and they
may be used in labelled or unlabelled form.
In its first aspect the invention provides novel diazabicyclic
biaryl derivatives represented by Formula I
##STR00001##
any of its enantiomers or any mixture of its enantiomers, or a
pharmaceutically acceptable salt thereof, wherein
n is 1, 2 or 3; and
'A'' represents a bivalent phenyl group of the formula
##STR00002##
'A'' represents a bivalent 5-membered aromatic monocyclic
heterocyclic group selected from
##STR00003## (read in the direction represented by ' and '');
wherein X represents O, S or Se; and R' represents hydrogen or
alkyl; or
'A'' represents a bivalent 6-membered aromatic monocyclic
carbocyclic or heterocyclic group selected from
##STR00004## (read in the direction represented by ' and '');
and
B represents an aromatic monocyclic or bicyclic carbocyclic group;
or
B represents a 5 6 membered aromatic monocyclic heterocyclic group;
or
B represents an aromatic bicyclic heterocyclic group;
which monocyclic or bicyclic, carbocyclic or heterocyclic groups
may optionally be substituted one or more times with substituents
selected from the group consisting of alkyl, cycloalkyl,
cycloalkyl-alkyl, alkoxy, cyanoalkyl, halo, CF.sub.3, OCF.sub.3,
CN, amino and nitro; and a group for formula --NR''COR''', and
--NR''SO2R''', wherein R'' and R''', independently of one another
represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or phenyl;
and a group of formula --CONR''R''' and --SO.sub.2NR''R''', wherein
R'' and R''', independently of one another represents hydrogen,
alkyl, cycloalkyl, cycloalkyl-alkyl or phenyl, or wherein R'' and
R''', together with the N-atom to which they are bound, form a
heterocyclic ring;
provided however,
if A represents an isoxazol-3,5-diyl, a thiazol-2,5-diyl, a
1,2,4-oxadiazol-3,5-diyl, a 1,3,4-oxadiazol-2,5-diyl, a
1,3,4-thiadiazol-2,5-diyl, pyridin-2,5-diyl, or a
pyridazin-3,6-diyl group, then B is not a phenyl or substituted
phenyl group; or
if A represents a 1,2,4-oxadiazol-3,5-diyl group, then B is not a
substituted or non-substituted thienyl, furanyl, pyridinyl, or
benzothienyl group.
In its second aspect the invention provides pharmaceutical
compositions comprising a therapeutically effective amount of the
diazabicyclic biaryl derivative of the invention, or a
pharmaceutically-acceptable addition salt thereof, together with at
least one pharmaceutically-acceptable carrier or diluent.
In a further aspect the invention relates to the use of the
diazabicyclic biaryl derivative of the invention, or a
pharmaceutically-acceptable addition salt thereof, for the
manufacture of a pharmaceutical composition/medicament for the
treatment, prevention or alleviation of a disease or a disorder or
a condition of a mammal, including a human, which disease, disorder
or condition is responsive to modulation of cholinergic receptors
and/or monoamine receptors.
In a final aspect the invention provides methods of treatment,
prevention or alleviation of diseases, disorders or conditions of a
living animal body, including a human, which disorder, disease or
condition is responsive to modulation of cholinergic receptors
and/or monoamine receptors, which method comprises the step of
administering to such a living animal body in need thereof a
therapeutically effective amount of the diazabicyclic biaryl
derivative of the invention.
Other objects of the invention will be apparent to the person
skilled in the art from the following detailed description and
examples.
DETAILED DISCLOSURE OF THE INVENTION
Diazabicyclic Biaryl Derivative
In a first aspect novel diazabicyclic biaryl derivatives are
provided. The diazabicyclic biaryl derivatives of the invention may
be represented by the general Formula I
##STR00005##
any of its enantiomers or any mixture of its enantiomers, or a
pharmaceutically acceptable salt thereof, wherein
n is 1, 2 or 3; and
'A'' represents a bivalent phenyl group of the formula
##STR00006## or
'A'' represents a bivalent 5-membered aromatic monocyclic
heterocyclic group selected from
##STR00007## (read in the direction represented by ' and '');
wherein X represents O, S or Se; and R' represents hydrogen or
alkyl; or
'A'' represents a bivalent 6-membered aromatic monocyclic
carbocyclic or heterocyclic group selected from
##STR00008## and (read in the direction represented by ' and '');
and
B represents an aromatic monocyclic or bicyclic carbocyclic group;
or
B represents a 5 6 membered aromatic monocyclic heterocyclic group;
or
B represents an aromatic bicyclic heterocyclic group;
which monocyclic or bicyclic, carbocyclic or heterocyclic groups
may optionally be substituted one or more times with substituents
selected from the group consisting of alkyl, cycloalkyl,
cycloalkyl-alkyl, alkoxy, cyanoalkyl, halo, CF.sub.3, OCF.sub.3,
CN, amino and nitro; and a group for formula --NR''COR''', and
--NR''SO2R''', wherein R'' and R''', independently of one another
represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or phenyl;
and a group of formula --CONR''R''' and --SO.sub.2NR''R''', wherein
R'' and R''', independently of one another represents hydrogen,
alkyl, cycloalkyl, cycloalkyl-alkyl or phenyl, or wherein R'' and
R''', together with the N-atom to which they are bound, form a
heterocyclic ring;
provided however,
if A represents an isoxazol-3,5-diyl, a thiazol-2,5-diyl, a
1,2,4-oxadiazol-3,5-diyl, a 1,3,4-oxadiazol-2,5-diyl, a
1,3,4-thiadiazol-2,5-diyl, pyridin-2,5-diyl, or a
pyridazin-3,6-diyl group, then B is not a phenyl or substituted
phenyl group; or
if A represents a 1,2,4-oxadiazol-3,5-diyl group, then B is not a
substituted or non-substituted thienyl, furanyl, pyridinyl, or
benzothienyl group.
In a preferred embodiment the diazabicyclic biaryl derivative of
the invention is a compound of Formula II
##STR00009##
wherein 'A'' and B are as defined above.
In another preferred embodiment the diazabicyclic biaryl derivative
of the invention is a compound of Formula I or Formula II,
wherein
'A'' is as defined above and
B represents an aromatic monocyclic or bicyclic carbocyclic group,
which aromatic group may optionally be substituted one or more
times with substituents selected from the group consisting of
alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyanoalkyl, halogen,
CF.sub.3, OCF.sub.3, CN, amino and nitro; or
B represents a 5 6 membered aromatic monocyclic heterocyclic group,
which aromatic group may optionally be substituted one or more
times with substituents selected from the group consisting of
alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyanoalkyl, halogen,
CF.sub.3, OCF.sub.3, CN, amino and nitro; or
B represents an aromatic bicyclic heterocyclic group, which
bicyclic heterocyclic group may optionally be substituted one or
more times with substituents selected from the group consisting of
alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyanoalkyl, halogen,
CF.sub.3, OCF.sub.3, CN, amino and nitro.
In a more preferred embodiment the diazabicyclic biaryl derivative
of the invention is a compound of Formula II wherein 'A'' is as
defined above; and
B represents a 5 6 membered aromatic monocyclic heterocyclic group;
or
B represents an aromatic bicyclic heterocyclic group;
which monocyclic or bicyclic heterocyclic groups may optionally be
substituted one or more times with substituents selected from the
group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
cyanoalkyl, halo, CF.sub.3, OCF.sub.3, CN, amino and nitro; and a
group for formula --NR''COR''', and --NR''SO.sub.2R''', wherein R''
and R''', independently of one another represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl or phenyl; and a group of formula
--CONR''R''' and --SO.sub.2NR''R''', wherein R'' and R''',
independently of one another represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl or phenyl, or wherein R'' and R''',
together with the N-atom to which they are bound, form a
heterocyclic ring.
In another preferred embodiment the diazabicyclic biaryl derivative
of the invention is a compound of Formula I or Formula II, wherein
B represents a phenyl or naphthyl group, optionally substituted one
or more times with substituents selected from the group consisting
of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyanoalkyl,
halogen, CF.sub.3, OCF.sub.3, CN, amino and nitro.
In a third preferred embodiment the diazabicyclic biaryl derivative
of the invention is a compound of Formula II wherein 'A''
represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00010## (read in the direction represented by ' and '');
wherein X represents O, S or Se; and R' represents hydrogen or
alkyl; and
B represents an aromatic monocyclic or bicyclic carbocyclic group,
which monocyclic or bicyclic carbocyclic groups may optionally be
substituted one or more times with substituents selected from the
group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
cyanoalkyl, halo, CF.sub.3, OCF.sub.3, CN, amino and nitro; and a
group for formula --NR''COR''', and --NR''SO.sub.2R''', wherein R''
and R''', independently of one another represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl or phenyl; and a group of formula
--CONR''R''' and --SO.sub.2NR''R''', wherein R'' and R''',
independently of one another represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl or phenyl, or wherein R'' and R''',
together with the N-atom to which they are bound, form a
heterocyclic ring.
In a more preferred embodiment
'A'' represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00011## (read in the direction stated),
wherein R' represents hydrogen or methyl; and
B represents a phenyl or naphthyl group, which aromatic group may
optionally be substituted one or two times with substituents
selected from the group consisting of alkyl, cycloalkyl,
cycloalkyl-alkyl, alkoxy, cyanoalkyl, halo, CF.sub.3, OCF.sub.3,
CN, amino and nitro; and a group for formula --NR''COR''', and
--NR''SO.sub.2R''', wherein R'' and R''', independently of one
another represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or
phenyl; and a group of formula --CONR''R''' and --SO.sub.2NR''R''',
wherein R'' and R''', independently of one another represents
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or phenyl, or wherein
R'' and R''', together with the N-atom to which they are bound,
form a piperidine, a piperazine, a morpholine or a thiomorpholine
ring.
In an even more preferred embodiment
'A'' represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00012##
B represents a phenyl or naphthyl group, which aromatic group may
optionally be substituted one or two times with substituents
selected from the group consisting of alkyl, alkoxy, halo,
CF.sub.3, OCF.sub.3, CN and nitro; and a group for formula
--NR''COR''', and --NR''SO.sub.2R''', wherein R'' and R''',
independently of one another represents hydrogen, alkyl or phenyl;
and a group of formula --CONR''R''' and --SO.sub.2NR''R''', wherein
R'' and R''', independently of one another represents hydrogen,
alkyl or phenyl, or wherein R'' and R''', together with the N-atom
to which they are bound, form a piperidine, a piperazine, a
morpholine or a thiomorpholine ring.
In a fourth preferred embodiment the diazabicyclic biaryl
derivative of the invention is a compound of Formula I or Formula
II wherein
'A'' represents a bivalent phenyl group of the formula
##STR00013## or
'A'' represents a 6-membered aromatic monocyclic carbocyclic or
heterocyclic group selected from
##STR00014## (read in the direction represented by ' and '');
and
B represents an aromatic monocyclic or bicyclic carbocyclic group;
or
B represents a 5 6 membered aromatic monocyclic heterocyclic group;
or
B represents an aromatic bicyclic heterocyclic group;
which monocyclic or bicyclic, carbocyclic or heterocyclic groups
may optionally be substituted one or more times with substituents
selected from the group consisting of alkyl, cycloalkyl,
cycloalkyl-alkyl, alkoxy, cyanoalkyl, halo, CF.sub.3, OCF.sub.3,
CN, amino and nitro; and a group for formula --NR''COR''', and
--NR''SO.sub.2R''', wherein R'' and R''', independently of one
another represents hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or
phenyl; and a group of formula --CONR''R''' and --SO.sub.2NR''R''',
wherein R'' and R''', independently of one another represents
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or phenyl, or wherein
R'' and R''', together with the N-atom to which they are bound,
form a heterocyclic ring.
In a more preferred embodiment 'A'' represents a bivalent phenyl
group of the formula
##STR00015## or
'A'' represents a 6-membered aromatic monocyclic carbocyclic or
heterocyclic group selected from
##STR00016## (read in the direction stated); and
B represents a phenyl or naphthyl group; or
B represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00017##
wherein X represents O, S or Se; and R' represents hydrogen or
alkyl; or
B represents a 6-membered aromatic monocyclic heterocyclic group
selected from
##STR00018##
B represents an indolyl group;
which phenyl or naphthyl groups, or 5 6-membered monocyclic
heterocyclic groups, or indolyl group may optionally be substituted
one or more times with substituents selected from the group
consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
cyanoalkyl, halo, CF.sub.3, OCF.sub.3, CN, amino and nitro; and a
group for formula --NR''COR''', and --NR''SO.sub.2R''', wherein R''
and R''', independently of one another represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl or phenyl; and a group of formula
--CONR''R''' and --SO.sub.2NR''R''', wherein R'' and R''',
independently of one another represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl or phenyl, or wherein R'' and R''',
together with the N-atom to which they are bound, form a
heterocyclic ring; or
which phenyl or naphthyl groups, or 5 6-membered monocyclic
heterocyclic groups, or indolyl group may optionally be substituted
one or more times with substituents selected from the group
consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
cyanoalkyl, halogen, CF.sub.3, OCF.sub.3, CN, amino and nitro.
In an even more preferred embodiment
'A'' represents a bivalent phenyl group of the formula
##STR00019## or
'A'' represents a bivalent 6-membered aromatic monocyclic
carbocyclic or heterocyclic group selected from
##STR00020## (read in the direction stated); and
B represents a phenyl group; or
B represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00021##
B represents a 6-membered aromatic monocyclic heterocyclic group
selected from
##STR00022##
B represents an indol-2-yl, an indol-3-yl, an indol-5-yl or an
indol-6-yl group;
which phenyl group, or 5 6-membered monocyclic heterocyclic groups,
or indolyl groups may optionally be substituted one or more times
with substituents selected from the group consisting of alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, CN and nitro; and a group for
formula --NR''COR''', and --NR''SO.sub.2R''', wherein R'' and R''',
independently of one another represents hydrogen, alkyl or phenyl;
and a group of formula --CONR''R''' and --SO.sub.2NR''R''', wherein
R'' and R''', independently of one another represents hydrogen,
alkyl or phenyl, or wherein R'' and R''', together with the N-atom
to which they are bound, form a a piperidine, a piperazine, a
morpholine or a thiomorpholine ring.
In a still more preferred embodiment 'A'' represents a bivalent
phenyl group of the formula
##STR00023## or
'A'' represents a bivalent 6-membered aromatic monocyclic
carbocyclic or heterocyclic group selected from
##STR00024## (read in the direction stated); and
B represents a phenyl group; or
B represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00025##
B represents a 6-membered aromatic monocyclic heterocyclic group
selected from
##STR00026## or
B represents an indol-2-yl, an indol-3-yl, an indol-5-yl or an
indol-6-yl group;
which phenyl group, or 5 6-membered monocyclic heterocyclic groups,
or indolyl groups may optionally be substituted one or more times
with substituents selected from the group consisting of alkyl,
alkoxy, halo, CF.sub.3, OCF.sub.3, CN and nitro; and a group for
formula --NR''COR''', and --NR''SO.sub.2R''', wherein R'' and R''',
independently of one another represents hydrogen, alkyl or phenyl;
and a group of formula --CONR''R''' and --SO.sub.2NR''R''', wherein
R'' and R''', independently of one another represents hydrogen,
alkyl or phenyl, or wherein R'' and R''', together with the N-atom
to which they are bound, form a a piperidine, a piperazine or a
morpholine ring.
In a yet more preferred embodiment
'A'' represents a bivalent phenyl group of the formula
##STR00027## or
'A'' represents a bivalent 6-membered aromatic monocyclic
carbocyclic or heterocyclic group selected from
##STR00028## (read in the direction stated); and
B represents a phenyl group; or
B represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00029##
B represents a 6-membered aromatic monocyclic heterocyclic group
selected from
##STR00030##
B represents an indol-2-yl, an indol-3-yl, an indol-5-yl or an
indol-6-yl group.
In a still more preferred embodiment
'A'' represents a bivalent phenyl group of the formula
##STR00031##
B represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00032##
wherein X represents O, S or Se; and R' represents hydrogen or
alkyl;
which 5-membered aromatic monocyclic heterocyclic group is
optionally substituted substituted one or more times with
substituents selected from the group consisting of alkyl, alkoxy,
halogen, CF.sub.3, CN and nitro.
In a most preferred embodiment the diazabicyclic biaryl derivative
of the invention is
4-(6-Thien-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Pyridin-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Selenophen-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-Biphenyl-4-yl-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Furan-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Thien-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Furan-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Thiazol-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Selenophen-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Indol-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Indol-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Indol-5-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-Indol-6-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-oxazol-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-oxazol-5-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(6-thiazol-5-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-[6-(1,3,4)-thiadiazol-2-yl-pyridazin-3-yl]-1,4-diazabicyclo[3.2.2]nonan-
e; or
4-[6-(1,3,4)-oxadiazol-2-yl-pyridazin-3-yl]-1,4-diazabicyclo[3.2.2]nonane-
;
or an enantiomer or a mixture of its enantiomers, or a
pharmaceutically acceptable salt thereof.
In a fifth preferred embodiment the diazabicyclic biaryl derivative
of the invention is a compound of Formula I or Formula II
wherein
'A'' represents a bivalent 5-membered aromatic monocyclic
heterocyclic group selected from
##STR00033## (read in the direction represented by ' and '');
wherein X represents O, S or Se; and R' represents hydrogen or
alkyl; and
B represents a 5 6 membered aromatic monocyclic heterocyclic group;
or
B represents an aromatic bicyclic heterocyclic group;
which monocyclic or bicyclic heterocyclic groups may optionally be
substituted one or more times with substituents selected from the
group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
cyanoalkyl, halo, CF.sub.3, OCF.sub.3, CN, amino and nitro; and a
group for formula --NR''COR''', and --NR''SO.sub.2R''', wherein R''
and R''', independently of one another represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl or phenyl; and a group of formula
--CONR''R''' and --SO.sub.2NR''R''', wherein R'' and R''',
independently of one another represents hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl or phenyl, or wherein R'' and R''',
together with the N-atom to which they are bound, form a
heterocyclic ring.
In a more preferred embodiment
'A'' represents a bivalent 5-membered aromatic monocyclic
heterocyclic group selected from
##STR00034## (read in the direction stated); and
B represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00035##
B represents a 6-membered aromatic monocyclic heterocyclic group
selected from
##STR00036##
which 5- or 6-membered aromatic monocyclic heterocyclic group is
optionally substituted one or two times with substituents selected
from the group consisting of alkyl, alkoxy halo, CF.sub.3,
OCF.sub.3, CN and nitro; and a group for formula --NR''COR''', and
--NR''SO.sub.2R''', wherein R'' and R''', independently of one
another represents hydrogen, alkyl or phenyl; and a group of
formula --CONR''R''' and --SO.sub.2NR''R''', wherein R'' and R''',
independently of one another represents hydrogen, alkyl or phenyl,
or wherein R'' and R''', together with the N-atom to which they are
bound, form a piperidine, a piperazine, a morpholine or a
thiomorpholine ring.
In an even more preferred embodiment
'A'' represents a bivalent 5-membered aromatic monocyclic
heterocyclic group selected from
##STR00037## (read in the direction stated); and
B represents a 5-membered aromatic monocyclic heterocyclic group
selected from
##STR00038##
B represents a 6-membered aromatic monocyclic heterocyclic group
selected from
##STR00039##
In a most preferred embodiment the diazabicyclic biaryl derivative
of the invention is
4-(5-Thien-2-yl-pyrrol-2-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(5-Thien-2-yl-N-methyl-pyrrol-2-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(5-Thien-2-yl-thiazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(2-Thien-2-yl-thiazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(5-Thien-2-yl-furan-2-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(5-Thien-2-yl-thien-2-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(5-Thien-2-yl-imidazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(5-Thien-2-yl-N-methyl-imidazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(2-Thien-2-yl-imidazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(2-Thien-2-yl-N-methyl-imidazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(5-Thien-2-yl-oxazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(2-Thien-2-yl-oxazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(5-Thien-2-yl-isoxazol-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(5-Thien-2-yl-isothiazol-3-yl)-1,4-diazabicyclo[3.2.2]nonane;
4-(3-Thien-2-yl-isoxazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane;
or
4-(3-Thien-2-yl-isothiazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane;
or an enantiomer or a mixture of its enantiomers, or a
pharmaceutically acceptable salt thereof.
Any combination of two or more of the embodiments described herein
is considered within the scope of the present invention.
Definition of Substituents
In the context of this invention halo represents a fluorine, a
chlorine, a bromine or an iodine atom. Thus, a trihalomethyl group
represents e.g. a trifluoromethyl group, a trichloromethyl group
and similar trihalo-substituted methyl groups.
In the context of this invention an alkyl group designates a
univalent saturated, straight or branched hydrocarbon chain. The
hydrocarbon chain preferably contain of from one to eighteen carbon
atoms (C.sub.1-18-alkyl), more preferred of from one to six carbon
atoms (C.sub.1-6-alkyl; lower alkyl), including pentyl, isopentyl,
neopentyl, tertiary pentyl, hexyl and isohexyl. In a preferred
embodiment alkyl represents a C.sub.1-4-alkyl group, including
butyl, isobutyl, secondary butyl, and tertiary butyl. In another
preferred embodiment of this invention alkyl represents a
C.sub.1-3-alkyl group, which may in particular be methyl, ethyl,
propyl or isopropyl.
In the context of this invention a cycloalkyl group designates a
cyclic alkyl group, preferably containing of from three to seven
carbon atoms (C.sub.3-7-cycloalkyl), including cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the context of this invention a cycloalkyl-alkyl group
designates a cycloalkyl group as defined above, which cycloalkyl
group is substituted on an alkyl group as also defined above.
Examples of preferred cycloalkyl-alkyl groups of the invention
include cyclopropylmethyl and cyclopropylethyl.
In the context of this invention an alkoxy group designates an
"alkyl-O--" group, wherein alkyl is as defined above. Examples of
preferred alkoxy groups of the invention include methoxy and
ethoxy.
In the context of this invention a cyanoalkyl group designates an
"-alkyl-CN" group, wherein alkyl is as defined above.
In the context of this invention an aromatic monocyclic or bicyclic
carbocyclic group designates a monocyclic or polycyclic aromatic
hydrocarbon group. Examples of preferred aryl groups of the
invention include phenyl, indenyl, naphthyl, azulenyl, fluorenyl,
and anthracenyl.
In the context of this invention a 5 6 membered aromatic monocyclic
heterocyclic designates a 5 6 membered heteroaryl, which holds one
or more heteroatoms in its ring structure. Preferred heteroatoms
include nitrogen (N), oxygen (O), and sulphur (S).
Preferred 5 6 membered heteroaryl groups of the invention include
furanyl, in particular 2- or 3-furanyl; thienyl, in particular 2 or
3-thienyl; selenophenyl, in particular 2- or 3-selenophenyl;
pyrrolyl (azolyl), in particular 2 or 3-pyrrolyl; oxazolyl, in
particular oxazol-2,4 or 5-yl; thiazolyl, in particular thiazol-2,4
or 5-yl; imidazolyl, in particular 2 or 4-imidazolyl; pyrazolyl, in
particular 3 or 4-pyrazolyl; isoxazolyl, in particular isoxazol-3,4
or 5-yl; isothiazolyl, in particular isothiazol-3,4 or 5-yl;
oxadiazolyl, in particular 1,2,3-oxadiazol-4 or 5-yl, or
1,3,4-oxadiazol-2-yl; triazolyl, in particular 1,2,3-triazol-4-yl
or 1,2,4-triazol-3-yl; thiadiazolyl, in particular
1,2,3-thiadiazol-4 or 5-yl, or 1,3,4-thiadiazol-2-yl; pyridinyl, in
particular 2,3 or 4-pyridinyl; pyridazinyl, in particular 3 or
4-pyridazinyl; pyrimidinyl, in particular 2,4 or 5-pyrimidinyl;
pyrazinyl, in particular 2 or 3-pyrazinyl; and triazinyl, in
particular 1,2,4- or 1,3,5-triazinyl.
In the context of this invention an aromatic bicyclic heterocyclic
group designates a bicyclic heterocyclic group, which holds one or
more heteroatoms in its ring structure. In the context of this
invention the term "bicyclic heterocyclic group" includes
benzo-fused five- and six-membered heterocyclic rings containing
one or more heteroatoms. Preferred heteroatoms include nitrogen
(N), oxygen (O), and sulphur (S).
Preferred bicyclic heteroaryl groups of the invention include
indolizinyl, in particular 2,5 or 6-indolizinyl; indolyl, in
particular 2,5 or 6-indolyl; isoindolyl, in particular 2,5 or
6-isoindolyl; benzo[b]furanyl, in particular 2,5 or 6-benzofuranyl;
benzo[b]thienyl, in particular 2,5 or 6-benzothienyl;
benzoimidazolyl, in particular 2,5 or 6-benzoimidazolyl;
benzothiazolyl, in particular 5 or 6-benzothiazolyl; purinyl, in
particular 2 or 8-purinyl; quinolinyl, in particular 2,3,6 or
7-quinolinyl; isoquinolinyl, in particular 3,6 or 7-isoquinolinyl;
cinnolinyl, in particular 6 or 7-cinnolinyl; phthalazinyl, in
particular 6 or 7-phthalazinyl; quinazolinyl, in particular 2,6 or
7-quinazolinyl; quinoxalinyl, in particular 2 or 6-quinoxalinyl;
1,8-naphthyridinyl, in particular 1,8-naphthyridin-2,3,6 or 7-yl;
and pteridinyl, in particular 2,6 or 7-pteridinyl.
Pharmaceutically Acceptable Salts
The diazabicyclic biaryl derivative of the invention may be
provided in any form suitable for the intended administration.
Suitable forms include pharmaceutically (i.e. physiologically)
acceptable salts, and pre- or prodrug forms of the chemical
compound of the invention.
Examples of pharmaceutically acceptable addition salts include,
without limitation, the non-toxic inorganic and organic acid
addition salts such as the hydrochloride, the hydrobromide, the
nitrate, the perchlorate, the phosphate, the sulphate, the formate,
the acetate, the aconate, the ascorbate, the benzenesulphonate, the
benzoate, the cinnamate, the citrate, the embonate, the enantate,
the fumarate, the glutamate, the glycolate, the lactate, the
maleate, the malonate, the mandelate, the methanesulphonate, the
naphthalene-2-sulphonate derived, the phthalate, the salicylate,
the sorbate, the stearate, the succinate, the tartrate, the
toluene-p-sulphonate, and the like. Such salts may be formed by
procedures well known and described in the art.
Metal salts of a chemical compound of the invention include alkali
metal salts, such as the sodium salt of a chemical compound of the
invention containing a carboxy group.
In the context of this invention the "onium salts" of N-containing
compounds are also contemplated as pharmaceutically acceptable
salts. Preferred "onium salts" include the alkyl-onium salts, the
cycloalkyl-onium salts, and the cycloalkylalkyl-onium salts.
Particularly preferred onium salts of the invention include those
created at the N' position according to the following formula
I'
##STR00040## Steric Isomers
The chemical compounds of the present invention may exist in (+)
and (-) forms as well as in racemic forms. The racemates of these
isomers and the individual isomers themselves are within the scope
of the present invention.
Racemic forms can be resolved into the optical antipodes by known
methods and techniques. One way of separating the diastereomeric
salts is by use of an optically active acid, and liberating the
optically active amine compound by treatment with a base. Another
method for resolving racemates into the optical antipodes is based
upon chromatography on an optical active matrix. Racemic compounds
of the present invention can thus be resolved into their optical
antipodes, e.g., by fractional crystallisation of d- or
l-(tartrates, mandelates, or camphorsulphonate) salts for
example.
The chemical compounds of the present invention may also be
resolved by the formation of diastereomeric amides by reaction of
the chemical compounds of the present invention with an optically
active activated carboxylic acid such as that derived from (+) or
(-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic
acid or by the formation of diastereomeric carbamates by reaction
of the chemical compound of the present invention with an optically
active chloroformate or the like.
Additional methods for the resolving the optical isomers are known
in the art. Such methods include those described by Jaques J,
Collet A, & Wilen S in "Enantiomers, Racemates, and
Resolutions", John Wiley and Sons, New York (1981).
Optical active compounds can also be prepared from optical active
starting materials.
Methods of Producing Diazabicyclic Biaryl Derivatives
The diazabicyclic biaryl derivative of the invention may be
prepared by conventional methods for chemical synthesis, e.g. those
described in the working examples. The starting materials for the
processes described in the present application are known or may
readily be prepared by conventional methods from commercially
available chemicals.
Also one compound of the invention can be converted to another
compound of the invention using conventional methods.
The end products of the reactions described herein may be isolated
by conventional techniques, e.g. by extraction, crystallisation,
distillation, chromatography, etc.
Biological Activity
The present invention relates to novel diazabicyclic biaryl
derivatives, which are found to be cholinergic ligands at the
nicotinic acetylcholine receptors (nAChR), and modulators of the
monoamine receptors, in particular the biogenic amine transporters
such as the serotonin receptor (5-HTR), the dopamine receptor (DAR)
and the norepinephrine receptor (NER), and of the biogenic amine
transporters for serotonin (5-HT), dopamine (DA) and norepinephrine
(NE). Also preferred diazabicyclic biaryl derivatives of the
invention show selective .alpha.7 activity.
In the context of this invention the term "modulator" covers
agonists, partial agonists, antagonists and allosteric modulators
of the receptor.
Due to their pharmacological profile the compounds of the invention
may be useful for the treatment of diseases or conditions as
diverse as CNS related diseases, PNS related diseases, diseases
related to smooth muscle contraction, endocrine disorders, diseases
related to neuro-degeneration, diseases related to inflammation,
pain, and withdrawal symptoms caused by the termination of abuse of
chemical substances.
In a preferred embodiment the compounds of the invention are used
for the treatment of diseases, disorders, or conditions relating to
the central nervous system. Such diseases or disorders includes
anxiety, cognitive disorders, learning deficit, memory deficits and
dysfunction, Alzheimer's disease, attention deficit, attention
deficit hyperactivity disorder, Parkinson's disease, Huntington's
disease, Amyotrophic Lateral Sclerosis, Gilles de la Tourette's
syndrome, depression, mania, manic depression, schizophrenia,
obsessive compulsive disorders (OCD), panic disorders, eating
disorders such as anorexia nervosa, bulimia and obesity,
narcolepsy, nociception, AIDS-dementia, senile dementia, periferic
neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia,
epilepsy, bulimia, post-traumatic syndrome, social phobia, sleeping
disorders, pseudodementia, Ganser's syndrome, pre-menstrual
syndrome, late luteal phase syndrome, chronic fatigue syndrome,
mutism, trichotillomania, and jet-lag.
In another preferred embodiment the compounds of the invention may
be useful for the treatment of diseases, disorders, or conditions
associated with smooth muscle contractions, including convulsive
disorders, angina pectoris, premature labour, convulsions,
diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia,
premature ejaculation, and erectile difficulty.
In yet another preferred embodiment the compounds of the invention
may be useful for the treatment of endocrine disorders, such as
thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.
In still another preferred embodiment the compounds of the
invention may be useful for the treatment of neurodegenerative
disorders, including transient anoxia and induced
neuro-degeneration.
In even another preferred embodiment the compounds of the invention
may be useful for the treatment of inflammatory diseases,
disorders, or conditions, including inflammatory skin disorders
such as acne and rosacea, Chron's disease, inflammatory bowel
disease, ulcerative colitis, and diarrhoea.
In still another preferred embodiment the compounds of the
invention may be useful for the treatment of mild, moderate or even
severe pain of acute, chronic or recurrent character, as well as
pain caused by migraine, postoperative pain, and phantom limb
pain.
Finally the compounds of the invention may be useful for the
treatment of withdrawal symptoms caused by termination of use of
addictive substances. Such addictive substances include
nicotine-containing products such as tobacco, opioids such as
heroin, cocaine and morphine, benzodiazepines and
benzodiazepine-like drugs, and alcohol. Withdrawal from addictive
substances is in general a traumatic experience characterised by
anxiety and frustration, anger, anxiety, difficulties in
concentrating, restlessness, decreased heart rate and increased
appetite and weight gain.
In this context "treatment" covers treatment, prevention,
prophylactics and alleviation of withdrawal symptoms and abstinence
as well as treatment resulting in a voluntary diminished intake of
the addictive substance.
In another aspect, the compounds of the invention are used as
diagnostic agents, e.g. for the identification and localisation of
nicotinic receptors in various tissues.
Pharmaceutical Compositions
In another aspect the invention provides novel pharmaceutical
compositions comprising a therapeutically effective amount of the
diazabicyclic biaryl derivative of the invention.
While a chemical compound of the invention for use in therapy may
be administered in the form of the raw chemical compound, it is
preferred to introduce the active ingredient, optionally in the
form of a physiologically acceptable salt, in a pharmaceutical
composition together with one or more adjuvants, excipients,
carriers, buffers, diluents, and/or other customary pharmaceutical
auxiliaries.
In a preferred embodiment, the invention provides pharmaceutical
compositions comprising the diazabicyclic biaryl derivative of the
invention, or a pharmaceutically acceptable salt or derivative
thereof, together with one or more pharmaceutically acceptable
carriers therefore, and, optionally, other therapeutic and/or
prophylactic ingredients, know and used in the art. The carrier(s)
must be "acceptable" in the sense of being compatible with the
other ingredients of the formulation and not harmful to the
recipient thereof.
The pharmaceutical composition of the invention may be administered
by any convenient route, which suits the desired therapy. Preferred
routes of administration include oral administration, in particular
in tablet, in capsule, in drage, in powder, or in liquid form, and
parenteral administration, in particular cutaneous, subcutaneous,
intramuscular, or intravenous injection. The pharmaceutical
composition of the invention can be manufactured by any skilled
person by use of standard methods and conventional techniques
appropriate to the desired formulation. When desired, compositions
adapted to give sustained release of the active ingredient may be
employed.
Further details on techniques for formulation and administration
may be found in the latest edition of Remington's Pharmaceutical
Sciences (Maack Publishing Co., Easton, Pa.).
The actual dosage depend on the nature and severity of the disease
being treated, and is within the discretion of the physician, and
may be varied by titration of the dosage to the particular
circumstances of this invention to produce the desired therapeutic
effect. However, it is presently contemplated that pharmaceutical
compositions containing of from about 0.1 to about 500 mg of active
ingredient per individual dose, preferably of from about 1 to about
100 mg, most preferred of from about 1 to about 10 mg, are suitable
for therapeutic treatments.
The active ingredient may be administered in one or several doses
per day. A satisfactory result can, in certain instances, be
obtained at a dosage as low as 0.1 .mu.g/kg i.v. and 1 .mu.g/kg
p.o. The upper limit of the dosage range is presently considered to
be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from
about 0.1 .mu.g/kg to about 10 mg/kg/day i.v., and from about 1
.mu.g/kg to about 100 mg/kg/day p.o.
Methods of Therapy
The diazabicyclic biaryl derivatives of the present invention are
valuable nicotinic and monoamine receptor modulators, and therefore
useful for the treatment of a range of ailments involving
cholinergic dysfunction as well as a range of disorders responsive
to the action of nAChR modulators.
In another aspect the invention provides a method for the
treatment, prevention or alleviation of a disease or a disorder or
a condition of a living animal body, including a human, which
disease, disorder or condition is responsive to modulation of
cholinergic receptors and/or monoamine receptors, and which method
comprises administering to such a living animal body, including a
human, in need thereof an effective amount of a diazabicyclic
biaryl derivative of the invention.
In the context of this invention the term "treatment" covers
treatment, prevention, prophylaxis or alleviation, and the term
"disease" covers illnesses, diseases, disorders and conditions
related to the disease in question.
The preferred indications contemplated according to the invention
are those stated above.
It is at present contemplated that suitable dosage ranges are 0.1
to 1000 milligrams daily, 10 500 milligrams daily, and especially
30 100 milligrams daily, dependent as usual upon the exact mode of
administration, form in which administered, the indication toward
which the administration is directed, the subject involved and the
body weight of the subject involved, and further the preference and
experience of the physician or veterinarian in charge.
A satisfactory result can, in certain instances, be obtained at a
dosage as low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The upper
limit of the dosage range is about 10 mg/kg i.v. and 100 mg/kg p.o.
Preferred ranges are from about 0.001 to bout 1 mg/kg i.v. and from
about 0.1 to about 10 mg/kg p.o.
EXAMPLES
The invention is further illustrated with reference to the
following examples, which are not intended to be in any way
limiting to the scope of the invention as claimed.
Example 1
Preparatory Example
All reactions involving air sensitive reagents or intermediates
were performed under nitrogen and in anhydrous solvents. Magnesium
sulfate was used as drying agent in the workup-procedures and
solvents were evaporated under reduced pressure.
1,4-Diazabicyclo[3.2.2]nonane (Intermediate Compound)
Was prepared according to J. Med. Chem. 1993 36 2311 2320 and the
following slightly modified method.
To a solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g, 113
mmol) in absolute dioxane (130 ml), LiAlH.sub.4 (4.9 g, 130 mmol)
was added under argon. The mixture was refluxed for 6 hours and
then allowed to reach room temperatre. To this reaction mixture,
water (5 ml in 10 ml of dioxane) was added, by drops, the mixture
was stirred for 0.5 hour and then filtered off via glass filter.
The solvent was evaporated and the residue was distilled using a
Kugelrohr apparatus at 90.degree. C. (0.1 mbar) to yield
1,4-diazabicyclo[3.2.2]nonane (11.1 g, 78%) as colourless
hygroscopic material.
1,4-Diazabicyclo[3.2.2]nonan-3-one (Intermediate Compound)
To a solution of 3-quinuclidinone hydrochloride (45 g, 278 mmol) in
90 ml of water, hydroxylamine hydrochloride (21 g, 302 mmol) and
sodium acetate (CH.sub.3COOH.times.3H.sub.2O, 83 g, 610 mmol) were
added, and the mixture was stirred at 70.degree. C. for 1 hour, and
then cooled to 0.degree. C. The separated crystalline material was
filtered off (without washing) and dried in vacuo to yield 40.0 g
of oxime.
The 3-quinuclidinone oxime (40.0 g) was added by small portions
during 2 hours to polyphosphoric acid* (190 g), preheated to
120.degree. C. During the reaction the temperature of the solution
was kept at 130.degree. C. After addition of all the oxime, the
solution was stirred for 20 minutes at the same temperature, then
transferred to an enamelled vessel and allowed to reach room
temperature. The acidic mixture was neutralized by a solution of
potassium carbonate (500 g in 300 ml of water), transferred into
2000 ml flask, diluted with 300 ml of water and extracted with
chloroform (3.times.600 ml). The combined organic extracts were
dried with sodium sulphate, the solvent evaporated, and the solid
residue dried up in vacuo to yield 30.0 g (77%) of a mixture of
lactams.
Crystallization of the obtained mixture from 1,4-dioxane (220 ml)
gave 15.8 g (40.5%) of 1,4-diazabicyclo[3.2.2]nonan-3-one as
colourless large crystals with mp 211 212.degree. C.
The filtrate was evaporated and the residue was chromatographed on
a silica gel column (Merck, 9385, 230 400 mesh) with acetone as
eluent. The solvent was evaporated and the residue recrystallised
from ethyl etanoate to yield 1,3-diazabicyclo[3.2.2]nonan-4-one
(10.2 g, 26%) as colourless fine crystals with mp 125 126.degree.
C.
Polyphosphoric Acid*
85% Orthophosphoric acid (500 g, 294 ml, 4.337 mol) was placed into
a 2000 ml flask and phosphor pentoxide (750 g, 5.284 mol) was added
at room temperature (ratio acid-pentoxide, 2:3). The mixture was
stirred at 200 220.degree. C. for 2 hours to yield of 1250 g of
polyphosphoric acid, containing 80% of P.sub.2O.sub.5.
3-Bromo-6-thien-3-yl-pyridazine (Intermediate Compound)
A mixture of 3,6-dibromo-pyridazine (8.45 g, 35.5 mmol),
palladacycle (0.66 g, 0.71 mmol), palladium acetate (0.16 g, 0.71
mmol), tri-tert-butylphosphine (0.35 ml, 1.42 mmol), aqueous
potassium carbonate (2 M, 107 mmol), 1,3-propanediol (7.7 ml, 107
mmol) and 1,4-dioxane (100 ml) was stirred at reflux for 1 hour.
3-Thienyl boronic acid (5.0 g, 39.0 mmol) was added and the mixture
was stirred at reflux for 7 days. Aqueous sodium hydroxide (50 ml,
1M) was added and the mixture was extracted with ethyl acetate
(2.times.100 ml). Chromatography on silica gel with ethyl
acetate:petroleum (1:3) as solvent gave the title compound. Yield
1.5 g (18%).
3-Chloro-6-thien-3-yl-pyridazine hydrochloric acid salt
(Intermediate Compound)
A mixture of 3-bromo-6-thien-3-yl-pyridazine (1.39 g, 5.8 mmol) and
conc. hydrochloric acid (25 ml) was stirred at reflux for 4.5
hours. The reaction mixture was evaporated and the product was
isolated in quantitative yield (1.35 g, 5.8 mmol).
4-(6-Bromo-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane fumaric
acid salt (Intermediate Compound)
A mixture of 3,6-dibromo-pyridazine (3.77 g, 15.85 mmol)
1,4-diazabicyclo[3.2.2]nonane (2.00 g, 15.85 mmol) and aqueous
sodium hydroxide (10 ml, 4M) was stirred at 100.degree. C. for 30
minutes. The mixture was extracted with dichloromethane (3.times.20
ml). Chromatography on silica gel with dichloromethane, 10%
methanol and 1% aqueous ammonia as solvent gave the title compound
as an oil. Yield 0.88 g, 20%.
4-[6-Thien-3-yl-pyridazin-3-yl]-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 1)
A mixture of 1,4-diazabicyclo[3.2.2]nonane (0.54 g, 4.29 mmol),
3-chloro-6-thien-3-yl-pyridazine hydrochloric acid salt (1.00 g,
4.29 mmol), triethylamine (3.00 ml, 21.4 mmol) and dioxane (15 ml)
was stirred at reflux for 40 hours. Aqueous sodium hydroxide (1 M,
25 ml) was added and the mixture was extracted twice with ethyl
acetate (2.times.20 ml). Chromatography on silica gel with
dichloromethane, 10% methanol and 1% aqueous ammonia as solvent
gave the title compound as an oil. The corresponding salt was
obtained by addition of a diethyl ether and methanol mixture (9:1)
saturated with fumaric acid. Yield 0.11 g, 9%. Mp 153.7.degree.
C.
Method A
4-(6-Pyridin-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 2)
A mixture of
4-(6-bromo-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane (0.49 g,
1.7 mmol), diethyl-3-pyridylborane (0.38 g, 2.6 mmol), aqueous
potassium carbonate (2.6 ml, 2M),
palladium(0)tetrakistriphenylphosphine (59 mg, 0.051 mmol),
1,3-propandiol (0.37 ml, 5.1 mmol) and dioxane (5 ml) was stirred
at reflux for 15 hours. The mixture was evaporated. Aqueous sodium
hydroxide (10 ml, 4M) was added. The mixture was extracted with
dichloromethane (3.times.20 ml). Chromatography on silica gel with
dichloromethane, 10% methanol and 1% aqueous ammonia as solvent
gave the title compound as an oil. Yield 0.10 g, 21%.
The corresponding salt was obtained by addition of a diethyl ether
and methanol mixture (9:1) saturated with fumaric acid. Mp 170.2
171.6.degree. C.
Method B
4-(6-Selenophen-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 3)
A mixture of
4-(6-bromo-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane (1.1 g,
3.9 mmol), 3-trimethylstannylselenophene (2.3 g, 7.8 mmol),
PdCl.sub.2(PPh.sub.3).sub.2 (82 mg, 0.11 mmol) and DMF (1 ml) was
stirred at 100.degree. C. for 15 hours. Aqueous sodium hydroxide
(10 ml, 4M) was added. The mixture was extracted with
dichloromethane (3.times.20 ml). Chromatography on silica gel with
dichloromethane, 10% methanol and 1% aqueous ammonia as solvent
gave the title compound as an oil. Yield 0.14 g, 11%.
The corresponding salt was obtained by addition of a diethyl ether
and methanol mixture (9:1) saturated with fumaric acid. Mp 181.2
182.2.degree. C.
4-(6-Thien-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 4)
Was prepared according to Method B from 2-trimetylstannylthiophene.
Mp 185.5 187.4.degree. C.
4-(6-Selenophen-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 5)
Was prepared according to Method B from
2-trimetylstannylselenophene. Mp 194.7 195.9.degree. C.
4-(6-Furan-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 6)
Was prepared according to Method B from 2-trimetylstannylfuran. Mp
155.7 156.1.degree. C.
4-(6-Furan-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 7)
Was prepared according to Method B from 3-trimetylstannylfuran. Mp
116.9 119.0.degree. C.
4-(6-Thiazol-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 8)
Was prepared according to Method B from 2-thiazolylzinc chloride.
Mp 175.2 179.2.degree. C.
In analogy herewith the following compounds are prepared:
4-(5-Thien-2-yl-pyrrol-2-yl)-1,4-diazabicyclo[3.2.2]nonane fumaric
acid salt (Compound 9);
4-(5-Thien-2-yl-N-methyl-pyrrol-2-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 10);
4-(5-Thien-2-yl-thiazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane fumaric
acid salt (Compound 11);
4-(2-Thien-2-yl-thiazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane fumaric
acid salt (Compound 12);
4-(5-Thien-2-yl-furan-2-yl)-1,4-diazabicyclo[3.2.2]nonane fumaric
acid salt (Compound 13);
4-(5-Thien-2-yl-thien-2-yl)-1,4-diazabicyclo[3.2.2]nonane fumaric
acid salt (Compound 14);
4-(5-Thien-2-yl-imidazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 15);
4-(5-Thien-2-yl-N-methyl-imidazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 16);
4-(2-Thien-2-yl-imidazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 17);
4-(2-Thien-2-yl-N-methyl-imidazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 18);
4-(5-Thien-2-yl-oxazol-2-yl)-1,4-diazabicyclo[3.2.2]nonane fumaric
acid salt (Compound 19);
4-(2-Thien-2-yl-oxazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane fumaric
acid salt (Compound 20);
4-(5-Thien-2-yl-isoxazol-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 21);
4-(5-Thien-2-yl-isothiazol-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 22);
4-(3-Thien-2-yl-isoxazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 23);
4-(3-Thien-2-yl-isothiazol-5-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 24);
4-(6-Indol-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 25);
4-(6-Indol-3-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 26);
4-(6-Indol-5-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 27);
4-(6-Indol-6-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 28);
4-(6-oxazol-2-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 29);
4-(6-oxazol-5-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 30);
4-(6-thiazol-5-yl-pyridazin-3-yl)-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 31);
4-[6-(1,3,4)-thiadiazol-2-yl-pyridazin-3-yl]-1,4-diazabicyclo[3.2.2]nonan-
e fumaric acid salt (Compound 32); and
4-[6-(1,3,4)-oxadiazol-2-yl-pyridazin-3-yl]-1,4-diazabicyclo[3.2.2]nonane
fumaric acid salt (Compound 33).
4-Biphenyl-4-yl-1,4-diazabicyclo[3.2.2]nonane fumaric acid salt
(Compound 34)
A mixture of 1,4-diazabicyclo[3.2.2]nonane (1.0 g, 7.9 mmol),
4-bromobiphenyl (1.85 g, 7.9 mmol), potassium tert-butoxide (1.85
g, 15.8 mmol), Pd(0)(PPh.sub.3).sub.4 (0.27 g, 0.24 mmol) and
dioxane (10 ml) was stirred at 100.degree. C. for 15 hours. The
mixture was evaporated. Aqueous sodium hydroxide (10 ml, 4M) was
added. The mixture was extracted with dichloromethane (3.times.20
ml). Chromatography on silica gel with dichloromethane, 10%
methanol and 1% aqueous ammonia as solvent gave the title compound
as an oil. Yield 65 mg, 3%.
The corresponding salt was obtained by addition of a diethyl ether
and methanol mixture (9:1) saturated with fumaric acid. Mp 196.3
196.9.degree. C.
Example 2
In Vitro Inhibition of .sup.3H-.alpha.-Bungarotoxine Binding in Rat
Brain
In this example the affinity of the compounds of the invention for
binding to .alpha..sub.7-subtype of nicotinic receptors is
determined.
.alpha.-Bungarotoxine is a peptide isolated from the venom of the
Elapidae snake Bungarus multicinctus. It has high affinity for
neuronal and neuromuscular nicotinic receptors, where it acts as a
potent antagonist.
.sup.3H-.alpha.-Bungarotoxine labels nicotinic acetylcholine
receptors formed by the .alpha..sub.7 subunit isoform found in
brain and the .alpha..sub.1 isoform in the neuromuscular
junction.
Tissue Preparation
Preparations are performed at 0 4.degree. C. Cerebral cortices from
male Wistar rats (150 250 g) are homogenised for 10 seconds in 15
ml of 20 mM Hepes buffer containing 118 mM NaCl, 4.8 mM KCl, 1.2 mM
MgSO.sub.4 and 2.5 mM CaCl.sub.2 (pH 7.5) using an Ultra-Turrax
homogeniser. The tissue suspension is subjected to centrifugation
at 27,000.times.g for 10 minutes. The supernatant is discarded and
the pellet is washed twice by centrifugation at 27,000.times.g for
10 minutes in 20 ml of fresh buffer, and the final pellet is then
re-suspended in fresh buffer containing 0.01% BSA (35 ml per g of
original tissue) and used for binding assays.
Assay
Aliquots of 500 .mu.l of homogenate are added to 25 .mu.l of test
solution and 25 .mu.l of .sup.3H-.alpha.-bungarotoxine (2 nM, final
concentration) and mixed and incubated for 2 hours at 37.degree. C.
Non-specific binding is determined using (-)-nicotine (1 mM, final
concentration). After incubation, the samples are added 5 ml of
ice-cold Hepes buffer containing 0.05% PEI and poured directly onto
Whatman GF/C glass fibre filters (pre-soaked in 0.1% PEI for at
least 6 hours) under suction, and immediately washed with 2.times.5
ml ice-cold buffer.
The amount of radioactivity on the filters is determined by
conventional liquid scintillation counting. Specific binding is
total binding minus non-specific binding.
The test value is given as an IC.sub.50 (the concentration of the
test substance which inhibits the specific binding of
.sup.3H-.alpha.-bungarotoxin by 50%).
The results of these experiments are presented in Table 1
below.
TABLE-US-00001 TABLE 1 Inhibition of .sup.3H-.alpha.-Bungarotoxine
Binding Compound No. IC.sub.50 (.mu.M) 1 0.038 4 0.044 5 0.0065 7
0.022 34 0.024
* * * * *